Meningococcus (N. meningitidis, Nm), a cause of epidemic meningitis and sepsis, is a commensal Gram-negative bacterium of the human nasopharynx. After bloodstream invasion, virulent encapsulated bacteria adhere to brain endothelial cells and proliferate onto the apical surface of host cells to form microcolonies at the site of initial bacterial attachment, then cross the Blood Brain Barrier (BBB) to colonize meninges (Nassif et al. 2002, Trends Microbiol, 10:227-232).
The main clinical feature of meningococcal infection is meningitis. Paradoxically, Neisseria meningitidis is a frequent asymptomatic colonizer of the human nasopharynx, and only a very small proportion of infections proceed to a sustained bacteraemia. In the majority of bacteremic patients the presence of N. meningitidis in the bloodstream will remain asymptomatic. However during the blood phase, the bacteria will interact with the brain endothelial cells and invade the meninges to be responsible for meningitis, which is the first clinical complication of meningococcal dissemination in 70% of patients. In 30% of bacteremic patients the presence of meningococci in the bloodstream will lead to clinical symptoms of septicemia with in some cases a purpura fulminans. In the latter case the bacteria cross the blood brain barrier; however, the meningitis symptoms are not at the forefront of the clinical presentation.
The emergence and epidemic potential of Nm are related to the expression of outer membrane components (capsular polysaccharide and lipooligosaccharide [endotoxin]), while the propensity of Nm to interact tightly with peripheral and brain vascular cells relies on the expression of type IV pili. These long filamentous structures, which extend from the bacterial cell surface, exhibit astonishing multifunctionality, including the attachment of virulent capsulated meningococci to cells and the triggering of host signalling events that contribute to the stabilization of bacterial colonies at the endothelial cell surface and promote subsequent translocation through endothelial barriers. Type IV pili are composed of hetero-multimeric pilin subunits, which are assembled into helical fibers by a complex machinery. They are comprised of the major pilin PilE required for piliation, and other low-abundance pilins (such as PilV, PilX or Comp) that structurally resemble PilE and modulate the pilus adhesive and signalling functions. The adhesive properties of type IV pili are also modulated by components of the pilus machinery such as the PilC1 allele, making it difficult to identify the molecular determinants involved in direct interaction with host cell receptors using a genetic approach. As a consequence, the precise adhesive components of the complex pilus structure remain undefined. However, it has been recently identified that the host G-protein-coupled β2-adrenergic receptor is an essential endothelial receptor for meningococcal type IV pili to trigger signalling events (Coureuil et al. 2010, Cell, 143:1149-1160; Lecuyer et al., 2011, Infect Immun, 80:175-186). Moreover, it has been identified that Nm colonies at the cell surface of a human brain endothelial cell line promote the translocation of Parrs to the inner surface of plasma membrane, facing bacteria. Parrs translocated under the colonies serve as a scaffolding platform for signaling events elicited by Nm. Among the GPCRs expressed in the cell line, only the β2-adrenoceptor (β2AR) plays a permissive role in the formation of cortical plaques under colonies and in bacterial crossing of cell monolayers. These observations reveal the requisition of a β2-adrenergic/β-arrestin signaling pathway by Nm to promote stable adhesion onto human brain endothelial cells and subsequent crossing of the BBB. More specifically, it has been shown that interaction of β2AR, in particular of the N-terminus of β2AR, with type IV pilus-associated proteins such as PilE or PilV, initiates the process allowing N. meningitidis to open and to traverse the BBB.
However, endothelial cells depleted of β2-adrenergic receptors still support bacterial adhesion, indicating that type IV pili promote the primary attachment of meningococci by interaction with another as yet unknown receptor.
Thus, preventing the primary attachment of meningococci to endothelial cells will prevent meningeal dissemination in the bloodstream, i.e. meningococcal bacteraemia, and/or meningococcal infection and, thereby will prevent bacterial meningitis and/or purpura fulminans. 